Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1

Cell Rep. 2023 Feb 28;42(2):112059. doi: 10.1016/j.celrep.2023.112059. Epub 2023 Jan 31.

Abstract

Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSCs), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSCs are the source of NEP. Importantly, NPY originates majorly from the splanchnic region and is cleaved by NEP in order to terminate contraction. Interestingly, NEP deficiency (Nep-/-) showed less fibrosis but portal hypertension upon liver injury in two different fibrosis models in mice. We demonstrate the incremental benefit of Nep-/- in addition to AT1R blocker (ARB) or ACE inhibitors for fibrosis and portal hypertension. Finally, oral administration of Entresto, a combination of ARB and NEP inhibitor, decreased hepatic fibrosis and portal pressure in mice. These results provide a mechanistic rationale for translation of NEP-AT1R-blockade in human liver fibrosis and portal hypertension.

Keywords: CP: Cell biology; cirrhosis; hepatic stellate cell; neprilysin; neuropeptide Y; neuropeptide Y receptor 1; portal hypertension; renin-angiotensin system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Animals
  • Fibrosis
  • Humans
  • Hypertension, Portal* / drug therapy
  • Liver Cirrhosis / drug therapy
  • Mice
  • Neprilysin
  • Neuropeptide Y*
  • Receptors, Neuropeptide Y

Substances

  • Neuropeptide Y
  • Receptors, Neuropeptide Y
  • Angiotensin-Converting Enzyme Inhibitors
  • Neprilysin
  • Angiotensin Receptor Antagonists